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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
A Phase IB Trial of Selinexor in Combination With Immune Checkpoint Blockade in Patients With Advanced Renal Cell
Omar Alhalabi1, Mohamed A Gouda2, Denái R Milton3
1Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Background:
Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.
Methods:
NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies. Arm M utilized twice weekly oral SEL and intravenous nivolumab (NIVO). Arm N utilized weekly oral SEL with NIVO plus ipilimumab (IPI). The primary objective of this study was to evaluate the safety of SEL + NIVO and SEL + NIVO+IPI. Secondary objectives included determining the objective response rate (ORR) and progression-free survival (PFS).
Results:
Twenty-nine patients were enrolled in the study, of which 26 (90%) had clear cell RCC (ccRCC). Most patients (72%, n = 21) had prior systemic therapies. All patients (100%) developed at least one treatment-emergent adverse event, and 93% had a treatment-related adverse event (TRAE). Grade ≥ 3 TRAE occurred in 31% of patients, including 10% with hyponatremia, 7% with neutropenia, and 7% with thromboembolic events. At a median follow-up of 12.4 months, the ORR in 27 patients evaluable for response was 19% (n = 5). An additional 17 patients (63%) had stable disease (SD) as the best response. The median PFS for the overall cohort was 14.5 months (95% CI 5.2-17.4 months; SEL + NIVO+IPI: 12.2 months, SEL + NIVO: 14.5 months). The median overall survival was 27.8 months (95% CI 15.3-32.5; SEL + NIVO+IPI: unreached, SEL + NIVO: 21.3 months).
Conclusions:
SEL in combination with NIVO or NIVO+IPI had a potentially favorable safety profile and showed modest clinical activity in patients with advanced renal cell carcinoma.
Trial Registration:
This clinical trial was registered on clinicaltrials.gov (NCT02419495).
Insights
Selinexor combined with nivolumab or nivolumab plus ipilimumab showed modest clinical activity in advanced renal cell carcinoma patients. The combination therapy demonstrated a potentially favorable safety profile in this phase IB study.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Selinexor (SEL) is a nuclear exportin 1 inhibitor impacting nuclear protein transport.
- Preclinical studies suggest SEL combined with checkpoint blockade may enhance immunotherapy response.
Purpose of the Study:
- Evaluate the safety of SEL in combination with nivolumab (NIVO) and ipilimumab (IPI).
- Assess the objective response rate (ORR) and progression-free survival (PFS) of these combinations.
Main Methods:
- Phase IB multiarm study (NCT02419495) in advanced malignancies.
- Two arms: twice-weekly oral SEL + IV NIVO, and weekly oral SEL + NIVO + IPI.
- Primary endpoint: safety; Secondary endpoints: ORR and PFS.
Main Results:
- 29 patients enrolled; 90% had clear cell RCC (ccRCC).
- 19% ORR observed in evaluable patients; 63% had stable disease (SD).
- Median PFS was 14.5 months; median overall survival was 27.8 months.
Conclusions:
- SEL combined with NIVO or NIVO+IPI demonstrated a potentially favorable safety profile.
- The combination therapy showed modest clinical activity in advanced renal cell carcinoma.
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